Update on ALS Flashcards
Definition of ALS
Age-dependent, progressive, lethal neurodegenerative disease
______ individuals in US have ALS
30,000
Median age of ALS at onset:
55
ALS is selective _____
death of motor neurons
ALS is muscle weakness affecting ___, ____, ____.
speech, swallowing, breathing
____ progression
Typical survival _____ years from onset
Rapid
2-3 years
ALS:
Type of onset: _____
Two types of onset:
Insidious
Extremities, “bulbar”
How does ALS progress
spreads to adjacent regions
Terminal phase of ALS complications?
respiratory failure, aspiration
ALS can present as
LMN: _____ (4 signs)
UMN: ______ (4 signs)
- Flaccid tone, atrophy, fasciculations, cramps
2. Spastic tone, increased DTRs, babinski, hoffman
Name the 5 “more or less” preserved functions in ALS
- Cognitive - unless frontotemporal dementia or bulbar affect
- Eye Movement
- Bladder/bowel
- Sexual function
- Sensation
ALS definition:
UMN and LMN signs co-existing in a single region. (85-90%)
ALS classification:
- If UMN only?
- IF LMN only?
- primary lateral sclerosis (PLS)
2. Progressive Muscular atrophy; progressive bulbar palsy
Medical management of ALS:
3
Rilutek
Vitamin E
Antioxidants
4 symptoms/complications often treated during ALS
Cramps
Fasciculations
Spasticity
drooling
ALS epidemiology:
Bimodal:
Gender:
Race:
65 years 2/100,000
M:F 1.6:1
Blacks ~60% of whites
Risk factors for ALS(4)
- Male gender 1.2-4:1
- Positive family history
- “clusters” - western pacific (Guam) ALS/PD
- Military service
“possible” additional risk factors for ALS (7)
- Neurotoxicant Exposures - Pb, Hg, pesticide, volatile solvents
- Occupations - electrical workers, farmers
- Trauma - skeletal trauma, fractures, severe electrical shock with unconsciousness
- Vigorous physical activity - heavy manual labor, athleticism
- Lifestyle factors - smoking, ETOH, BMI
- Diet - highfat intake, glutamate intake, low fiber, antioxidant intake
- Infecious agents, home pesticide exposure, residential proximity to industry.
ALS spares which cranial nerves and nucleus?
3/4/6 and Onuf’s nucleus
Name the two cytoplasmic inclusions of ALS
Bunina bodies
Ubiquitin-positive inclusions
(axonal spheroids)
7 theories behind pathogenesis of ALS
- Protein toxicity: FALS, SOD1
- Oxidative stress - excess production or impaired degradation of reactive oxidized species from metals, molecules, and cellular organelles
- Mitochondrial abnormalities
- Glutamate excitotoxicity
- Neurofilament aggregation, axonal transport
- RNA processing (TDP-43, FUS)
- Repeat Expansion (C9orf72) - hexagonal repeat
Sporadic cases account for ___% of ALS.
90
Median age of onset for familial ALS (FALS)
25% associated with defect in: ____-
35
Autosomal Dominant
Cu, Zn Superoxide dismutase (SOD1) - over 100 mutations defined at SOD1 locus
Most common mutation in SOD1 for ALS?
4 others?
A4V is most common SOD1 mutation in North American Other genes; FUS TDP-43 ANG Fig4
Mutations in the ____gene on Chromosome 16
FUS/TLS - fused in sarcoma/translated in liposarcoma gene
Function of FUS/TLS gene
In ALS. Protein normally binds to RNA, functions in diverse processes, and is normally located in predominantly the nucleus. Mutant forms accumulate in cytoplasm of neurons
What appears to be common pathogenic mechanism of ALS on a genetic level?
neuronal cytoplasmic protein aggregation and defective RNA metabolism.
Number 1 drug therapy in ALS.
How does it work? 3
Rilutek (riluzole):
- Inhibitory effect on glutamate release
- inactivationof voltage-dependent sodium channels
- ability to interfere with intracellular events that follow transmitter binding at excitator amino acid receptors.
